ABSTRACT The RAS family of genes, comprised of KRAS, NRAS, and HRAS, are mutated in upwards of a third of all human cancers, yielding proteins that remain in a constitutively active, oncogenic state that are well established to cause this disease. The proteins encoded by these three genes are nearly identical, activated by and signal through the same proteins, and capable of causing cancer in mice. Despite this uniformity, KRAS is the most commonly mutated of the three, and the type of mutations in KRAS, as well as the other RAS genes, varies extensively in human cancers. To understand these phenomena, we compared the nucleotide sequence of the RAS genes, finding that KRAS has many rare codons that limit protein expression, HRAS has many common codons that foster protein expression, while NRAS has a mixture of rare and common codons and intermediate protein expression. Focusing on KRAS, the most commonly mutated RAS gene, we show that introducing silent mutations to convert rare codons to common in one exon of this gene reduced both the number of lung tumors and the mutations detected in Kras of mice exposed to a carcinogen. To determine the mechanism responsible for this result, in aim 1 we will activate an inducible oncogenic Kras gene with common codons in the lungs of mice to identify the stage of tumorigenesis sensitive to perturbing the inherent rare codon bias of Kras. Once identified, we will then hone in on the cellular feature changed, and in turn, the molecular response underlying this effect. Converting rare codons to common also altered the type of oncogenic mutations recovered in Kras after carcinogen exposure. To determine the underlying mechanism, in aim 2 we will similarly engineer mice with an inducible Kras gene encoded by common versus native codons with different oncogenic mutations. As above, these Kras alleles will be activated in the lungs of mice to determine how different oncogenic mutations in the backdrop of altered codon usage impacts tumorigenesis, tumor cell characteristics, and cellular signaling. Completion of these two aims will elucidate the mechanism by which codon bias influences the frequency and type of mutations arising in Kras during tumorigenesis. Despite the advantage afforded to Kras by rare codons in early tumorigenesis, we show that established cancer cells overcome the poor translation of Kras mRNA imposed by rare codons to increase Kras protein expression, which was linked to increased tumorigenic activity and resistance to chemotherapeutics. To identify how cancer cells achieve this feat, we screened for and identified codon- dependent modifiers of oncogenic Ras in the model organism Drosophila. We will capitalize on these candidate modifiers in aim 3 to elucidate how cancer cells overcome poor translation of Kras, and in turn, whether such changes promote more malignant phenotypes. In summary, this research will reveal how this novel feature of KRAS, codon bias, impacts tumorigenesis.